Evaluation of DNA Binding Drugs as Inhibitors of ESX, and ETS Domain Transcription Factor Associated With Breast Cancer: Effects of ESX/DNA Complex Disruption
Abstract
DNA binding agents, sequence preference and sequence specific, were evaluated for their ability to inhibit ESX binding to the HER2/neu promoter and down regulate cancer associated gene expression. Cell-free mobility shift assay results revealed that the sequence specific agents to be far superior to the sequence preference agents at inhibiting transcription factor/DNA complex formation. However, cell-free transcription results did not maintain this order of potency, with each group of agent more equally effective at inhibiting HER2/neu regulated expression. Whole-cell analysis, employing techniques such as northern blot analysis and cytotoxicity. revealed no cellular activity by the sequence specific agents. Conversely, for the sequence preference agents the whole- cell studies revealed a general pattern of potency of G/C sequence preference agents compared to A/T preference agents at inhibiting cellular mRNA levels of the targeted gene HER2/neu and on cellular growth. In depth analysis has revealed polyamide 22 to be cell permeable and localize to the nucleus. Continued studies are underway to determine the nuclear target of polyamide 22 binding. Examination of the structural changes of polyamides and the resultant effect on cellular localization and biological activity are underway and could influence the continued design of these potential therapeutic agents.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2000
- Accession Number
- ADB266038
Entities
People
- Stephanie Leslie
- Terry Beerman
Organizations
- Health Research, Incorporated